Welcome to the American College of Toxicology s Webinar Series

Transcription

1 Welcome to the American College of Toxicology s Webinar Series

2 Thank You to Our Co-sponsors British Toxicology Society Society of Toxicologic Pathology

3 Drug Metabolite(s) Safety Tes>ng Fred Alavi, Ph.D. The Division of Metabolism and Endocrinology Products United States Food and Drug Administra>on Disclaimer: Views expressed here are those of the author and not the FDA.

4 Metabolite Safety Tes>ng Objec>ves of this webinar Describe what a dispropor;onal or unique human metabolite is in safety tes;ng Determine the value of safety tes;ng of metabolites Iden;fy when it s necessary to characterize metabolites Define the type of metabolite safety studies that may be needed Define the excep;ons to the rules Slide 4

5 Regulatory Guidance Background Evolu;on of regulatory guidelines: Historical approach- - case by case evalua;on DruSafe subcommihee mee;ng (2000) PhRMA MIST posi;on paper (Baillie et al, 2002) FDA Guidance for Industry: Safety Tes;ng of Drug Metabolites (2008) ICH- M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceu;cals (2010, supersedes 2008 FDA guidance) ICH- M3 (R2) Q&A sec;on on metabolites (2013) hhp:// GuidanceComplianceRegulatoryInforma;on/Guidances/default.htm Slide 5

6 Dispropor>onal and Unique Metabolites Defini>on Dispropor;onal human metabolite: Exposure substan;ally ( 2x) higher in humans than in animals Unique human metabolite: Only observed in humans Slide 6

7 Why do safety tes>ng of the metabolites Historically, toxicological and toxicokine;c evalua;ons have focused on ac;ve pharmaceu;cal ingredient (API) due in part to insensi;ve analy;cal methods and contribu;on of metabolites to overall drug toxicity Metabolites across species are o`en similar and require no independent toxicity tes;ng (reason not to do tes;ng) High doses in animals generally cover exposure levels to dispropor;onal human metabolites (reason not to do further tes;ng) Pre- Guidance Metabolite Safety Tes;ng case by case Slide 7

8 Why do safety tes>ng of the metabolites Parent and metabolites contribute to target organ toxicity Differences in the metabolite exposure can result in different toxicity profile. Delayed characteriza;on of dispropor;onal human metabolite may increase safety risk and delay drug registra;on New technologies (HPLC/MS/MS) permit early and accurate characteriza;on of metabolites Differences in drug metabolizing enzymes across species Slide 8

9 Species Differences in CYP450 enzymes P450 Human Mouse Rat Dog Monkey CYP1A2 X X X X X CYP2B6 X CYP2C9 X (12%)* X CYP2C19 X CYP2D6 X (31%)* CYP2E1 X X X X X CYP3A4 X (50%)* * Percentage of drugs metabolized by each CYP enzyme in humans Mar;goni, 2006 Guengerich, 1997 Slide 9

10 Why do safety tes>ng of the metabolites Phase I human metabolites are more likely to pose a safety risk than phase II metabolites (i.e. glucuronide, glutathione conjugates) Pharmacologically ac;ve metabolite may contribute to overall drug pharmacology and toxicity Pharmacologically inac;ve metabolites are not devoid of toxicity thus require toxicological assessment Slide 10

11 Timing of the Drug Metabolite Characteriza>on Slide 11

12 Characterizing Metabolites- - Timing In vitro profiling in test animals and humans before first dose in human study In vitro studies may not concur with in vivo metabolite profile In vivo metabolite characteriza;on in humans prior to large scale clinical trials Compare in vivo metabolite profiles across species Steady state metabolite exposure is required when nonclinical data suggest metabolite/drug accumula;on Single dose radiolabeled study may be used to extrapolate to steady state exposure Slide 12

13 Human Metabolite Decision Chart Slide 13

14 Metabolite exposure greater than 10% of total drug exposure will need further considera>on: q Dispropor;onal human metabolite exposure is less than 2x the animal exposure q Dispropor;onal human metabolite exposure is 2 x animal exposure q Metabolite exposure only seen in humans Slide 14

15 Dispropor>onal Human Metabolite: Factors to consider: Any known toxicity risk Poten;al for genotoxicity Extent of human exposure compared to test species Does the metabolite accumulate with repeated dosing? Reliability and valida;on of the analy;cal assay Synthesis of the metabolite Alternate animal model Background knowledge of the drug class Slide 15

16 Unique Human Metabolites Factors to consider: Extent of human exposure Single dose vs. mul;ple dose exposure Knowledge of the metabolic pathway Biliary exposure in animals Alternate animal model Any new adverse clinical signal Genotoxicity poten;al Slide 16

17 Unique Animal Metabolites Occasionally animals may form a metabolite(s) not detected in humans that may cause toxicity in animals, not relevant to humans. Consider Number of species the metabolite is formed Alternate animal model Iden;fica;on of the metabolic pathway in animals is necessary to exclude toxicity signal relevant to humans Slide 17

18 Points to consider before tes>ng Metabolite is pharmacologically ac;ve or inac;ve Metabolite is unique or dispropor;onal In vitro verses in vivo metabolite profile For drug doses <10 mg/day, greater frac;on of the drug related material might be more appropriate trigger for tes;ng Is metabolite a phase I or phase II product Phase II products- generally less toxic, more water soluble (glucuronide and gluthathione, metabolites with hydroxyl group) vs. more toxic reac;ve acyl glucuronide metabolites Slide 18

19 Nonclinical Studies to Assess the Safety of Dispropor>onal / Unique Human Metabolites Slide 19

20 Nonclinical Studies with Human Metabolite Safety pharmacology studies are not needed unless a new signal iden;fied in humans, not observed in animals Genotoxicity- ü In silico QSAR (Quan;ta;ve Structural- Ac;vity Rela;onship) assessment ü In vivo micronucleus or relevant genotox test General toxicity study in single relevant species (4 to 13 weeks) Embryofetal development study in single relevant species (rat or rabbit) Slide 20

21 Nonclinical Studies with the Human Metabolite Carcinogenicity study in mouse or rat ü Metabolite may be added to parent drug ü Metabolite exposure in carcinogenicity study should provide at least 50% of the exposure seen in humans ü Use of transgenic animal model may be acceptable for carcinogenicity assessment of human metabolite Slide 21

22 Possible Excep>ons to the Rules Some safety tes;ng of metabolites for drugs for life threatening diseases may be waived The 10% rule may not apply for drugs that are extensively metabolized with minimal parent drug exposure The 10% rule may not apply for metabolites with genotoxicity poten;al Metabolites of the phase II metabolism may exceed the 10% rule (i.e. glucuronide metabolites) Previous experience and suppor;ve data for some phase I metabolites may not require rigorous tes;ng (case by case basis) Slide 22

23 Possible Excep>ons to the Rules Embryofetal development study for dispropor;onal metabolite may not be necessary for teratogenic parent drug Jus;fied scien;fically supported data may be used to wave/reduce metabolite safety tes;ng (i.e. similar to parent drug, low overall exposure, metabolites from similar drug class) Slide 23

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25 A Case Example: Phase II Human Metabolite Early in vitro metabolism profile found metabolism among species to be qualita;vely and quan;ta;vely similar In vivo studies found two dispropor;onally high glucuronide metabolites in humans with minimal or no exposure in animals. In vivo human metabolites were iden;fied as o- glucuronide metabolites, rapidly filtered by the kidney. Ac>on: No further nonclinical assessment was deemed necessary Slide 25

26 A Case Example: Phase I and II metabolites 2 Dispropor;onal (Phase I and II) human metabolites iden;fied Phase I accounted for more than ½ of total drug exposure in plasma Phase II metabolite was not considered a safety risk Ac>on: Clinical study was terminated un;l clarifica;on of the metabolite safety Nonclinical assessment of the Phase I metabolite was ini;ated (genotoxicity, standard toxicology, embryofetal development study..) Slide 26

27 A Case Example: Inac>ve Human Metabolites In vitro: 2 primary hydroxylated (M1, M2) and 2 secondary oxida;ve metabolite (M3, M4) in humans, monkeys, dogs, rats and mice In vivo: no notable M4 exposure in rats or mice In vivo: monkey M4 exposure 1/3 of parent with new toxicity signal (~60% of the human exposure) In vivo: human M4 exposure 4x the parent drug Ac>on: In vitro genotoxicity with M4 (M4 was genotoxic) Toxicology studies in rats with M4 Embryofetal development study in rat with M4 Carcinogenicity assessment of the M4 Slide 27

28 Summary The unique or dispropor;onal human metabolites are rela;vely rare. In vitro profiling of drug metabolites should be conducted before first dose in humans In vivo profiling of metabolites should be resolved before large scale clinical trials. Safety tes;ng of drugs with unique/dispropor;onally higher human metabolites exceeding the 10% the total drug- related product exposure need to be addressed. Overall, early human metabolite characteriza;on can lead to quicker resolu;on of metabolite safety issues. Slide 28

29 References Baillie T, et al. Drug metabolites in safety tes;ng. Toxicol Appl Pharmacol Aug 1;182(3): Robison TW and Jacobs A, Metabolites in safety tes;ng. Bioanalysis Oct;1(7): Gao H, et al. Mee;ng report: metabolites in safety tes;ng (MIST) symposium- safety assessment of human metabolites: what's REALLY necessary to ascertain exposure coverage in safety tests? AAPS J Oct;15(4):970-3 Mar;goni, Groothuis and de Kanter. Species differences between mouse, rat, dog, monkey and human CYP- mediated drug metabolism, inhibi;on and induc;on Expert Opin Drug Metab Toxicol. 2006, 2: Guengerich FP. Comparisons of cataly;c selec;vity of cytochrome P450 subfamily enzymes from different species. Chem Biol Interact Oct 24;106(3): Davis- Bruno K and Atrakchi A. regulatory perspec;ve on issues and approaches in characterizing human metabolites. Chem Res Toxicol Dec;19(12): Frederick CB and Obach RS. Metabolites in Safety Tes;ng: MIST for the Clinical Pharmacologist. Transla;onal Medicine (Nature), 2010 Mar; 87(3) Regan et al. Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos Oct;31(7): US FDA Guidance for Industry: Safety Tes;ng of Drug Metabolites, 2008 ICH- M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceu;cals 2010 ICH- M3(R2) Q&A (R2), Nonclinical Safety Studies for the Conduct of Human Clinical Trials, 2013 hhp:// Slide 29

30 Thank you for your participation in the American College of Toxicology Webinar! We hope to see you at the 35th Annual Meeting of the American College of Toxicology Slide 30